The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the invention.
T cell receptors recognize foreign antigens which have been processed as small peptides and bound to major histocompatibility complex (MHC) molecules at the surface of antigen presenting cells (APC). Each T cell receptor is a dimer consisting of one alpha and one beta chain or one delta and one gamma chain. The human T-cell receptor gamma (TCR-γ) locus is located on chromosome 7 (7p14) and includes V (variable), J (joining), and C (constant) segments (Lefranc et al. Curr. Top. Microbiol. Immunol. 1991; 173: 3-9).
To date 14 V gene (V γ) segments (TRGV1, TRGV2, TRGV3, TRGV4, TRGV5, TRGV5P, TRGV6, TRGV7, TRGV8, TRGVA, TRGV9, TRGV10, TRGVB, TRGV11), including 6 pseudogenes have been identified upstream to five J gene (J γ) segments (TRGJP1, TRGJP, TRGJ1, TRGJP2, and TRGJ2), and two C gene (C γ) segments (TRGC1 and TRGC2) in the TCR-γ locus (Lefranc et al. Nature. 1985; 316: 464-466; Lefranc et al. Cell. 1986; 45: 237-246; Quertermous et al. Science. 1986; 231: 252-255; Forster et al. EMBO J. 1987; 6: 1945-1950; Huck et al. EMBO J. 1988; 7(3): 719-726). Several V segments of the gamma locus are known to be incapable of encoding a protein and are considered pseudogenes.
Rearrangement of TCR-γ genes is an important part of thymocyte development. During T cell development, the gamma chain is synthesized by a recombination event at the DNA level joining a V segment with a J segment; the C segment is later joined by splicing at the RNA level. Recombination of many different V segments with several J segments provides a wide range of antigen recognition. The status of TCR-γ gene rearrangements helps define developmental stages. Analysis of TCR-γ gene rearrangement can be used to detect clonality in a T-cell population (Signoretti et al. Am. J. Pathol. 1999; 154: 67-75; Chain et al. J. Immunol. Methods. 2005; 300(1-2): 12-23).
Clonality is not synonymous with malignancy because it can be detected in non-neoplastic lymphocytic infiltrates (Wood et al. J Invest Dermatol. 1994; 103: 34-41). Nevertheless, it is generally accepted that most neoplasms are clonal in origin. Thus, detection of clonal cells with identical rearrangement favors a diagnosis of malignancy. Peripheral T-cell lymphomas arise from T cells that undergo malignant transformation after most rearrangements of TCR loci are completed. T-cell clonality estimation is important for the differential diagnosis between malignant and nonmalignant T-cell proliferation (Diss et al. J Clin Pathol. 1995; 48: 1045-1050; Signoretti et al. Am. J. Pathol. 1999; 154: 67-75; Gra et al. J. Mol. Diagn. 2007; 9: 249-257).